TABLE 1.
Clinical description of patients with KCNA1 variants functionally characterized
| Patient | Genetic findings | Clinical findings | Described in: | Additional references | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Nucleotide change (NM_000217) | Amino acid substitution | gnomAD frequency | Inheritance | Functional domain | Phenotype | Age at seizure onset | Age at last \follow‐up | Seizure types/treatments used | EEG findings | Brain MRI | Additional clinical features | |||
| 1/M | c.1213C > T | p. Pro405Ser | — | de novo | S6 – PVP motif | Epileptic encephalopathy with severe cognitive impairment | 3 m | 5 y | 3 m: back arching spells; 5 m: brief staring spell that was followed by flaccidity of the arms and legs; 18 m: prolonged episodes (>30 min) with unresponsiveness and leftward eye deviation, with or without clonic movements; 5 y: 3 to 4 prolonged seizures per year, often precipitated by fever; /PB, Clob, CBZ, ZSM and VPA, all ineffective | 3 m: generalized slowing;18 m: subclinical seizure with left parietal onset, high‐amplitude, multifocal epileptiform abnormalities and generalised slowing | 3 m: symmetric subdural fluid collections and prominent subarachnoid spaces; 5 y: normal | Developmental delay, mild to moderate axial and appendicular hypotonia, increased insertional activity consistent with irritable motor nerves at electromyography but without classic myokymic discharges. | Rogers et al., 2018 | — |
| 2/F | c.1214C > T | p. Pro405Leu | — | de novo | S6 – PVP motif | Epileptic encephalopathy with severe cognitive impairment | 18 d | 7 y 6 m | 18 d: generalized clonic; 2 m: generalized tonic‐clonic seizures; 4 y: focal onset impaired awareness seizures; often precipitated by fever; PB, CBZ, LEV, and PHT all ineffective or very short benefit | 18 d: severe epileptiform discharges on both hemispheres; 4 y: multifocal abnormalities, with left temporal predominance; 7 y: severe bilateral independent epileptiform discharges, with status epilepticus during sleep (ESES) responsive to ACTH | normal | Developmental delay, autism spectrum disorder, moderate‐severe intellectual disability, distal tremor and impaired coordination of cerebellar origin | Parrini et al., 2017 | Russo et al., 2020 |
| 3/M (identical twin brother of Patient 4) | c.1207C > T | p. Pro403Ser | — | de novo | S6 – PVP motif | Generalized epilepsy, moderate cognitive impairment & myokymia | 6 m | 20 y | 6 m: generalized tonic‐clonic seizures; LTG partially effective, multiple additional medications not specified, all ineffective | NA | 6 m: normal | Developmental delay, ataxia, intellectual disability severe recurrent headaches | Rogers et al., 2018 | — |
| 4/M (identical twin brother of Patient 3) | c.1207C > T | p. Pro403Ser | — | de novo | S6 – PVP motif | Epilepsy, severe cognitive impairment & myokymia | 4 m | 20 y | Generalized tonic‐clonic and absence seizures; LTG, GVG, OXC, VPA, PHT, and Clob, all ineffective | NA | 2 y: high signal intensities in the globus pallidus, slightly delayed myelination | Developmental delay, ataxia, myokymia, moderate intellectual disability. Between 8–12 y, language loss and walk only with support | Rogers et al., 2018 | — |
| 5/F | c.781G > A | p. Ala261Thr | — | de novo | S3 | Focal epilepsy responsive to carbamazepine | 7 y | 18 y |
Focal occipital seizures with blurred vision, complex hallucinations and, at times, fading hearing; secondarily generalized tonic‐clonic seizures Seizure precipitation during fever; VPA transiently effective, CBZ effective |
Bilateral, right predominant, occipital spikes | 8 y: normal | None | This paper | Yuan et al., 2020 |
Abbreviations: CBZ, carbamazepine; Clob, clobazam; d, days; F, female; GVG, vigabatrin; LTG, lamotrigine; M, male; m, months; NA, not available; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; VPA valproic acid; y, years; ZSM, zonisamide.